Lipid-dependent regulation of human Th17 cell function

人类 Th17 细胞功能的脂质依赖性调节

• 批准号: 9176733
• 负责人: Jun R. Huh
• 金额: $ 44.27万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176733
• 关键词: Adverse effects; Arthritis; Autoimmune Diseases; Autoimmune Process; Biogenesis; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chemicals; Colitis; Cytoplasm; Data; Development; Disease; Disease model; Effector Cell; Family; Fatty Acids; Fatty Liver; Gene Expression; Gene Targeting; Genes; Genetic Screening; Genetic screening method; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Kinetics; Lead; Ligands; Light; Link; Lipids; Liver diseases; Memory; Metabolic; Metabolism; Modeling; Molecular; Multiple Sclerosis; Mus; Nonesterified Fatty Acids; Nuclear Hormone Receptors; Organelles; Orphan; PPAR gamma; Pathology; Pathway interactions; Physiological; Play; Polyunsaturated Fatty Acids; Production; Proteins; Psoriasis; Regulation; Regulatory T-Lymphocyte; Retinoids; Role; Specificity; Sterols; T cell differentiation; T-Lymphocyte; Testing; Triglycerides; abstracting; chemical genetics; cytokine; gain of function; knock-down; lipid metabolism; macromolecule; novel; novel therapeutics; programs; receptor; response; small hairpin RNA; small molecule; treatment strategy

Abstract Th17 cells are an Interleukin-17-producing subset of CD4+ T effector cells that are centrally implicated in many human inflammatory and autoimmune diseases, from inflammatory bowel disease to multiple sclerosis. The retinoid orphan receptor gamma t (RORγt), a nuclear hormone receptor, programs Th17 cell development and function. With the ultimate goal of modulating inflammatory T cells in disease settings, we undertook chemical and genetic screening to identify RORγt target genes that drive human Th17 cell function. Intriguingly, our results implicated a group of genes in a novel pathway that would link lipid metabolism, RORγt activity and Th17 cell functions. We will thus test the hypothesis that Th17 cell function is controlled in large part, by RORγt target genes, via lipid droplets (LDs) (cellular organelles associated with lipid metabolism). We will take the following approaches: First, we will determine if LD- related genes – specifically, HILPDA and BNIP3 – are necessary, sufficient and specific regulators of human Th17 cell functions. Second, we will elucidate the molecular mechanisms by which LDs modulate Th17 cell differentiation. Third, using autoimmune disease models in mice, we will determine the physiological significance of LDs in inflammation and autoimmune pathologies. Our results may shed a light on novel lipid-regulatory mechanisms that control Th17 cell responses in inflammatory diseases.

抽象的 Th17 细胞是 CD4+ T 效应细胞的产生 Interleukin-17 的子集，集中分布于 与许多人类炎症和自身免疫性疾病有关，例如炎症性肠病 疾病发展为多发性硬化症。类维生素A孤儿受体γt（RORγt），一种核激素 受体，控制 Th17 细胞的发育和功能。最终目的是调节 疾病环境中的炎症 T 细胞，我们进行了化学和基因筛查 识别驱动人类 Th17 细胞功能的 RORγt 靶基因。有趣的是，我们的结果 暗示一组基因参与了一条连接脂质代谢、RORγt 活性的新途径 和 Th17 细胞功能。因此，我们将检验 Th17 细胞功能受控的假设 大部分是由 RORγt 靶基因通过脂滴 (LD)（与 脂质代谢）。我们将采取以下方法：首先，我们将确定是否与 LD 相关。 基因——特别是 HILPDA 和 BNIP3——是必要的、充分的和特定的调节因子 人类 Th17 细胞功能。其次，我们将阐明LDs的分子机制。 调节 Th17 细胞分化。第三，利用小鼠自身免疫疾病模型，我们将 确定 LD 在炎症和自身免疫病理学中的生理意义。 我们的结果可能有助于揭示控制 Th17 细胞的新型脂质调节机制 炎症性疾病的反应。